Renal injuries or disease, such as acute kidney failure or chronic kidney failure, can result from a variety of different causes (such as illness, injury, and the like).
Acute kidney injury (AKI) is a rapid loss of kidney function. AKI is so far diagnosed on the basis of clinical history, like decreased urine production, elevated blood urea nitrogen and creatinine. AKI can lead to numerous complications, including metabolic acidosis, high potassium levels, changes in body fluid balance, and effects to other organ systems. AKI is observed in 5% of hospitalized patients and associated with a high mortality.
The molecular mechanisms of tubular regeneration after ischemic renal injury remain largely unknown. An understanding of the mechanisms that lead to renal cell proliferation and regeneration will be necessary for the exploration of novel therapeutic strategies for the treatment of ischemic AKI. Some reports have proposed that regeneration processes may recapitulate developmental processes to restore organ or tissue function. The adult tubular epithelial cells have a potent ability to regenerate after cellular damage. Under a condition of ischemic renal damage, normally quiescent cells undergo dedifferentiation and acquire the ability to proliferate after their DNA synthesis is enhanced.
AKI begins by inducing molecular modifications later evolving into cellular damage. The cells start producing markers of injury and the clinical syndrome develops subsequently. Biomarker expression represents an earlier stage in progression to clinical syndrome (Ronco et al., 2008). Thus, detection of biomarkers may provide the much needed window of opportunity for early intervention. Based on the differential expression of the biomarkers, it is also likely that the biomarker panels will distinguish between the various types and etiologies of AKI. Possible newer biomarkers of AKI can be components of serum or urine or can be imaging studies or any other quantifiable parameter. New biomarkers are likely to be useful in facilitating early diagnosis, guiding targeted intervention and monitoring disease progression and resolution.
The early identification and treatment of renal injuries and disease would be useful in preventing disease progression. Currently, serum creatinine is frequently used as a biomarker of kidney function. However, serum creatinine measurements are influenced by muscle mass, gender, race and medications. Unfortunately, these limitations often result in the diagnosis of kidney disease only after significant damage has already occurred.
The diagnosis and prognosis of acute kidney injury (AKI) by current clinical means is inadequate (Parikh et al., Ann Clin Biochem 2010; 47: 301-312). In an effort to enhance diagnosis, biomarkers for the early detection of acute kidney injury have recently been introduced into clinical practice. These biomarkers, such as NGAL (Mishra et al., J Am Soc Nephrology, vol. 14, 2003) or Kim-1, can be detected in urine, serum or kidney biopsies and, when levels of the biomarkers are elevated, allow acute kidney injury detection within 2-4 hours of the precipitating event (e. g. surgery, shock, sepsis, nephrotoxin administration). In this regard, the newly introduced biomarkers (e. g. NGAL, Kim-1) outperform conventional biomarkers (e. g. serum creatinine, blood urea nitrogen), which are elevated only later in the course of kidney injury. However, both the conventional and newly introduced biomarkers known in the art at the present time exhibit the significant disadvantage, that their expression is elevated for an extended time after acute kidney injury (in some cases more than 7 days after injury). Recent studies outline that NGAL for example is still strongly expressed long after injury (Krawczeski, et al, 2011, Journal of Pediatrics, 158(6):1009), in some cases more than 120 hours after injury (Mishra et al., Lancet 2005; 365: 1231-38).
Therefore, the biomarkers currently available exhibit expression profiles that enable identification that acute kidney injury has occurred at some point in the past, but allow neither a precise estimate of the time point of the precipitating event nor estimation or determination of the temporal stage of kidney regeneration. Large-scale approaches have been published, in which a number of genes or proteins are disclosed as being relevant biomarkers for detection of kidney injury, albeit only for detection of injury. Sufficient detail on the conciseness of expression profiles and their relation to the temporal phase of injury or regeneration in order to provide an accurate determination of injury time is not provided (WO 2009/083950 A2, WO 2009/127644 A1). Other biomarkers for AKI such as Keratinocyte-derived chemokine (Molls et al., Am J Physiol Renal Physiol 290:F1187-F1193, 2006) also show expression long after injury, thereby preventing use of such markers for determination of injury time or temporal phase after injury.
The biomarkers of the present invention relate to Chac1, Birc5 and Angptl7. Chac1 has been disclosed as useful in identifying substances that are active in preventing or treating a disease associated with a malfunction of carbohydrate or lipid metabolism (WO 2006/094735 A1) and has not previously been related to kidney disease. Birc5 has been implicated in kidney regeneration (WO 2006/051075 A1) and prevention of apoptosis in kidneys (Kindt et al., FASEB J. 2008 February; 22(2):510-21), although no mention has been made of Birc5 as a biomarker with the specific properties disclosed herein. Angptl7 has until now only been disclosed in relation to expression in human eyes in glaucoma patients (Kuchtey et al., IOVS, vo. 49, no. 8, 2008, Peek et al., Invest. Opthalmology & Vis. Science, vol. 39, no. 10, 1998). The inventive properties of the biomarkers of the present invention, which enable the method of the present invention, have been neither suggested nor disclosed by the prior art.
Known biomarkers, such as NGAL, can be seen as useful and early indicators for kidney injury, which remain present for very long times after injury. The biomarkers of the present invention and their use in a method of determining temporal phase, enable, in light of the known markers, the determination of more specific phases of injury and regeneration within the broad window of NGAL or creatinine expression.
In clinical practice, the time point of the precipitating event is frequently unknown. Hence, there is a need for biomarkers that allow a precise determination of the time point of acute kidney injury and facilitate a temporal staging of the disease.